The Section is developing novel therapies using isolation organ perfusion of the extremity or liver using tumor necrosis factor (TNF) and melphalan for the treatment of primary or metastatic cancer confined to these regions. The complete response rate in patients treated with TNF and melphalan via isolated limb perfusion is 80% compared to a melphalan alone perfusion of 63%. A Phase II trial is ongoing using TNF based regimens in isolated limb perfusion to treat patients with intransit melanoma after a failed prior limb perfusion and patients with high-grade unresectable extremity sarcoma. The Section has been conducting a Phase I/II trial of isolated hepatic perfusion (IHP) using TNF and melphalan for the treatment of metastatic or primary unresectable cancers confined to the liver. In the Phase II portion of the trial the overall response rate is 80%. In order to prolong the duration of responses in patients with metastatic colorectal cancer confined to the liver, a new trial of IHP with melphalan and TNF combined with postoperative intra-arterial floxuridine has been initiated. The toxicities associated with IHP are acceptable. The laboratory has been conducting research studies to characterize the antitumor effects of TNF. We have shown that endothelial cells in vitro release significant quantities of tissue factor and increase expression of VCAM in response to TNF. Using a Xenon clearance in vivo blood flow model we have shown that TNF will result in a significant and sustained decrease in blood flow through tumor associated neovasculature. These data show that there are significant endothelial cell responses to TNF in vitro and in tumor associated neovasculature. VEGF and EMAP are tumor derived cytokines that may influence the sensitivity of tumors to the antitumor effects of TNF. Murine and human tumor lines in culture and in vivo express these cytokines in amounts that correspond to TNF cytotoxicity in vivo. Recently the ob gene has been cloned which encodes a circulating satiety factor. Our laboratory has investigated the regulation of the ob gene in adipose tissue during acute and chronic inflammatory diseases. Administration of TNF, IL-1, endotoxin or cecal ligation and puncture all result in upregulation of the ob gene suggesting its role in the anorexia of disease.
